Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation

被引:8
|
作者
Merino, Beatriz [1 ]
Casanueva-Alvarez, Elena [1 ]
Quesada, Ivan [2 ,3 ]
Gonzalez-Casimiro, Carlos M. [1 ]
Fernandez-Diaz, Cristina M. [4 ]
Postigo-Casado, Tamara [1 ]
Leissring, Malcolm A. [5 ]
Kaestner, Klaus H. [6 ,7 ]
Perdomo, German [1 ]
Cozar-Castellano, Irene [1 ,3 ]
机构
[1] Univ Valladolid CSIC, Unidad Excelencia Inst Biol & Genet Mol, Valladolid, Spain
[2] Univ Hernandez Elche, Inst Invest, Desarrollo & Innovac Biotecnol Sanit Elche IDiBE, Elche, Spain
[3] Ctr Invest Biomed Red Diabet & Enfermedades Metab, CIBERDEM, Madrid, Spain
[4] CEI UAM CSIC, IMDEA Food Inst, Madrid, Spain
[5] Univ Calif Irvine, Inst Memory Impairments & Neurol Disorders, UCI MIND, Irvine, CA USA
[6] Univ Penn, Dept Genet, Philadelphia, PA USA
[7] Univ Penn, Inst Diabet Obes & Metab, Philadelphia, PA USA
基金
美国国家卫生研究院;
关键词
Alpha cells; Cytoskeleton; Hyperglucagonaemia; Insulin-degrading enzyme; Primary cilia; Proliferation; Type; 2; diabetes; GLUCOSE-HOMEOSTASIS; PRIMARY CILIA; GENE; HYPERSECRETION; ISLETS; MICE; MAFB;
D O I
10.1007/s00125-022-05729-y
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Aims/hypothesis Type 2 diabetes is characterised by hyperglucagonaemia and perturbed function of pancreatic glucagon-secreting alpha cells but the molecular mechanisms contributing to these phenotypes are poorly understood. Insulin-degrading enzyme (IDE) is present within all islet cells, mostly in alpha cells, in both mice and humans. Furthermore, IDE can degrade glucagon as well as insulin, suggesting that IDE may play an important role in alpha cell function in vivo. Methods We have generated and characterised a novel mouse model with alpha cell-specific deletion of Ide, the A-IDE-KO mouse line. Glucose metabolism and glucagon secretion in vivo was characterised; isolated islets were tested for glucagon and insulin secretion; alpha cell mass, alpha cell proliferation and alpha-synuclein levels were determined in pancreas sections by immunostaining. Results Targeted deletion of Ide exclusively in alpha cells triggers hyperglucagonaemia and alpha cell hyperplasia, resulting in elevated constitutive glucagon secretion. The hyperglucagonaemia is attributable in part to dysregulation of glucagon secretion, specifically an impaired ability of IDE-deficient alpha cells to suppress glucagon release in the presence of high glucose or insulin. IDE deficiency also leads to alpha-synuclein aggregation in alpha cells, which may contribute to impaired glucagon secretion via cytoskeletal dysfunction. We showed further that IDE deficiency triggers impairments in cilia formation, inducing alpha cell hyperplasia and possibly also contributing to dysregulated glucagon secretion and hyperglucagonaemia. Conclusions/interpretation We propose that loss of IDE function in alpha cells contributes to hyperglucagonaemia in type 2 diabetes.
引用
收藏
页码:1375 / 1389
页数:15
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